Certain 1-aralkyl azetidines

ABSTRACT

A NOVEL SERIES OF SUBSTITUTED 1-(PHENYLISOPROPYL)-3,3DIMETHYL AZETIDINES USEFUL AS APPETITE DEPRESSANTS.

U.S. Cl. 260--239 A 4 Claims ABSTRACT OF THE DISCLOSURE A novel seriesof substituted 1-(phenylisopropyl)-3,3- dimethyl azetidines useful asappetite depressants.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is acontinuation-in-part of copending U.S. Ser. No. 684,492, filed Nov. 20,1967, and now abandoned.

DETAILED DESCRIPTION OF THE INVENTION This invention is directed tonovel series of chemical compounds, and more particularly, to a novelseries of substituted a-methylphenethyl azetidines.

The compound of this invention may be generally represented by thestructural formula CH CH wherein R and R are the same J1 dilferentmembers of the group consisting of hydrogen, chlorine, fluorine andtrifluoromethyl. In addition to the foregoing, R and R when takentogether at the 3- and 4-positions respectively, may form a cycloalkylring having from 3 to 5 carbon atoms and when taken together at the 4-and 5-positions respectively, may form a methylenedioxy ring system.These compounds may be prepared as the free bases, or more conveniently,as the pharmaceutically acceptable acid-addition salts.

The term pharmaceutically acceptable acid-addition salts, as usedherein, refers to the non-toxic salts which are prepared by reacting thefree base with an organic or inorganic acid. Representative saltsinclude the hydrochloride, hydrobromide, sulfate, bisulfate, acetate,valerate, oleate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, 'fumarate, succinate, tartrate and the like.

Generally, these compounds are prepared by reacting an appropriatelysubstituted a-methylphenethyl-3-halo-2, Z-disubstituted propionamidewith a reducing agent in an inert solvent. This reaction results in acyclization of the terminal portion of the molecule forming theazetidine compound. The disubstituted propionamide intermediatecompounds have the general structural formula "nited States Patent Osuch N-substituted-3-halo-2,2-dimethyl may be prepared. Table Ifollowing below contains a few 3,649,618 Patented Mar. 14, 1972 icewherein R and R are as previously defined and R is a memberindependently selected from the group consisting of alkyl and aryl.These compounds are prepared by reacting an appropriately substitutedct-methylphenethyl amine with a halo-2,2-disubstituted propionyl halide.The reac tion may be represented as follows:

wan

As indicated above, the intermediate compounds are prepared by reactinga substituted ot-methylphenethyl amine with a halo-2,2-disubstitutedpropionyl halide wherein the disubstitution may be with alkyl, aryl oran alkyl group and an aryl group on the 5 carbon atom. However, thepropionyl halide derivative having methyl as each of the R substituentsis most conveniently utilized since this acid is commercially available.It is to be understood, of course, that the reaction will proceed as setforth herein where each R is selected from either alkyl or aryl.

In order to more clearly illustrate the novel compounds of thisinvention, reference is made to the following examples which areintended to demonstrate but a few specific embodiments of the inventionand not to limit the same thereby.

Example 1.3-chloro-2,2-dimethyl-N- [a-methyl-3- (trifluoromethylphenethyl] propionamide To a chilled mixture of 40.5 grams (0.2 molar)of ozmethyl-3-trifiuoromethyl-phenethylamine, 20.2 grams (0.2 molar) oftriethylamine and 500 ml. anhydrous ether is added 31.0 grams (0.2molar) of fJ-chloropropionyl chloride dropwise with stirring. Themixture is stirred in the cold for 2 hours, washed twice with water, andthe ether layer dried over anhydrous magnesium sulfate. The drying agentis removed, the ether stripped and the crude residue air-dried.

The crude product is further purifiedby taking same up in ether, washingthe ethereal solution with 50 ml. of 3% hydrochloric acid, then withwater, then with 50 ml. of 3% sodium hydroxide solution, and finallyagain with water. The ethereal solution is then' dried over anhydrousmagnesium sulfate. The drying agent is removed, the ether stripped and awater-white residue crystallizes slowly on chilling; yielding 61.5 gramsof 3-chloro-2,2-dimethyl-N- [ct-methyl 3(trifluoromethyl)phenethyl]propionamide having a melting point of 5860C.

Following the procedure of Example 1, various other propionamidesrepresentative species prepared in this manner, along With theidentifying physical constants of each.

' TABLE 1 Analysis, percent Calculated Found Empirical M1. in

Ex. Compound formula C. H N C H N 3-ohloro2,2-dlmethyl-N-[a-methyl-4-ohlorophenethyllproplonamide. CnHwClzNO 120.5-12L558.35 6.64 4.86 58.21 6.66 4.71 3-chloro-2,2-d1methyl-N{a-methyl-3-ehlorophenethyl]propionamide OHH CIZNO 58.5-60.558.38 6.64 4.86 58.63 6.68 5.03

3-caililfigg22dimethyl-N-[mmethyl-3,4-(d1chloro)-phenethyl] propion-CnHisC e o 95-97 52-12 .3 3 A 5 3-chloro-2,2'dimethyl-N-[a-methyl-4-fluorophenethyl] roplonamide. CHHIBCIFNO77-79 61.88 7.05 5.15 61.56 7.07 4.96 3chloro-2,2-dimethyl-N-{a-methyl-3-fiuoro-phenethyl propionamide.-.CnHmClFNO 81-845 61.88 7.04 5.15 61.65 7.08 5.28 7.-....Elclgloro-Zfi-dimd ethyl-N-[a-methyl-t-(trifiuoromethyl)phenethyl1pro-CH1QC1F3NO 100-101 56.00 5. 96 4.35 56. 09 5. 90 4.38

ponarm e. 8 3-tgilpria-2hm2-dimethyl-N-[a-methyl-4,E-(methylenedloxy)-phenethyl]CrsHzflClNOa 88-90 60.50 6.77 4.70 60.33 6.66 4.71

pon e. 9 3-chloro-N-[2(5-indanyl)-l-methylene]-2,2-dimethylproplonamideCllHflClFNO 113-114 69.49 8.23 4.76 69.42 8 02 4.86

Example l0.-1-(phenylisopropyl)-3,3-dimethylazetidine A solution of 37.2grams (0.125 molar) of 3-bromo-2,2-dimethyl-N[a-methylphenethyl]propionamide in 450 ml. of anhydrousether is added dropwise to a suspension of 9.5 grams (0.25 molar) oflithium aluminum hydride in 100 ml. of anhydrous ether at a rate tomaintain reflux, and stirred at room temperature for 5% hours. Thelithium aluminum hydride complex and excess lithium aluminum hydride aredecomposed of dropwise consecutive addition of 9 ml. of water, 9 ml. of15% sodium hydroxide solution and 27 ml. of water to the chilledreaction mixture while stirring and the mixture is stirred for anadditional A hour. The solid is removed by filtration and washed withether. The combined filtrate and washings are dried over magnesiumsulfate. After removing the drying agent, the ether is stripped and theresidue distilled. A fraction having a boiling point of 88-115 C. at 1.5mm. of pressure, N 1.4953 is obtained yielding a total of 28 grams of 1(phenylisopropyl)-3,3-dimethyl azetidine. N.M.R. and LR. data confirmedthe identity of the compound.

Following the procedure of Example 10, a number of other azetidinederivatives may be prepared having one or more radicals substituted onthe phenyl ring. In Table fumarate, oxalate, and other suchacid-addition salts may be prepared.

The free bases, as well as the acid-addition salts of the azetidinecompounds, exhibit good activity as anorectic agents when administeredorally or subcutaneously at dosages of between l-SO milligrams perkilogram of body weight. The test procedure utilized to illustrate thisbio logical activity is relatively simple. Two groups consisting of fourrats each are placed on a five-hour feeding schedule; that is, the totalfeeding period for a 24 hour period is 5 hours for each group at thesame time of the day, seven days a week. Approximately /2 hour beforethe feeding time is to commence, the control group is administered astandard dosage of saline solution and the test group is administered adosage of one of the test compounds. A measured amount of feed is givento both groups (the same amount for each group) and at the end of the 5hour feeding period, the food remaining is measured to determine intake.

In Table III following below is given the activity data found for arepresentative number of the compounds of this invention. In each case,the percentage figure represents the percent of food intake less thanthe controls at the expressed dosage level.

TABLE III Percent intake Dosage, less than LD Compound mgJkg. controlsmgJkg.

3 51 10 59 1. l-(phenylisopropyl)-3,3-dimethyl azetidine-HCI g. g; 300

82 2. l-(tehlorophenylisopropyl)-3,3-dimethy1 azatidine'HCl ,3 g; 500 3.1-(3,4-dichlorophenylisopropyl)-3,3-dimethyl azetidine- H01 12 13 300 4.l-(Mluorophenylisopropyl)-3,3-dimethyl azetrdine-HCI. 10 28 500 5.1-(4-fiuorophenylisopropyl)-3'dimethyl azetidme- H01- 10 21 300 6.1-(4-trifluoromethyl phenylisopropyl)-3,3-d1rnethyl azetidm 14 26 750 IIbelow are listed a representative number of other such azetidinesprepared from the correspondingly substituted3-halo-2,Z-dimethyl-phenethyl propionamide along the identifyingphysical constants of each. In each case, N.M.R. and LR. data confirmedthe identity of the compound.

The column headed LD mg./kg. in Table 111 above, indicates the oraldisage in milligrams per kilogram of body weight, which is lethal to 50%of the test animals. In the above experiment, the test compounds wereadministered via the oral route, although other routes ofadministration, such as subcutaneous, intraperitoneal, and intra- TABLEII Analysis Calculated Found Empirical Compound formula B.P. 111C. 0 H NH N 1-(4-chlorophenylisopropyl)-3,3-dimethyl azetidine CnHmOlN 110-124at 1.1 mm. pressure..- 70.72 8. 48 5. 89 70. 74 8.71 5.71-(3-ohlorophenylisopropyl)-3,3-dimethylazetidine..- CHHMOIN116120at1.9rnm.pressure. 70.72 8.48 5. 89 70. 99 8.62 5. 991-(3,4-diehlorophenylisopropyl)-3,3-dimethylazetidine.OnHnClzN138141at1.5mm.pressure 61.78 7.03 5.14 61.60 7.09 5.25'1-(4-fiuorophenylisopropyl) 3,3-dlmethylazetidine-.. CnH FN8791at1.5mm.pressure. 75.98 9.11 6.33 75.69 9.13 6.531-(3-fiuorophenylisopropyl)-3,3-dirnethyl azetidine CuHmFN 87-90 at1.4mm.prcssure.- 75.98 9.11 6. 33 70. 69 9.14 6.431-(4-trifluoromethylphenyl isopropyl)-8,3-dimethyl azetidine..-CisHznFaN 97-103 at 1.3 mm. pressure 66.40 7. 43 5.16 65.84 7. 68 5.411-(3-trifiuoromethylphenyl1sopropyl)-3,3-dimethyl azetidine.-- CuHzoFaN93-103 at 2.0 mm.pfessure 66.40 7.43 5.16 66.17 7.43 5. 291-(4-5-methyleuedioxy-phenyl isopropyl)-3,3-dimethyl azetidine CmHzrNOz136-142at1.3mm.pressure.. 72.84 8.56 5.66 72.75 8.33 5.69 191-[2(5-indanyl)-1-methyleneethyl]-3,3-dimethylazetidine CnHnN 133-137 at1.3 mm. pressu e... 83. 90 10.3 5 5. 83.65 10. 49 5.83

muscular, among others, may be successfully employed. Furthermore, thecompounds were administered in the form of their hydrochlorideacid-addition salts for the reason that these salts are verywater-soluble and therefore CH CH CH-N l CH wherein R and R are eachmembers independently selected from the group consisting of hydrogen,chlorine, fluorine, trifluoromethyl, and R and R taken together at the4- and 5-positions forming a methylene dioxy ring, and R and R takentogether at the 3- and 4-positions forming a cycloalkyl ring having from3 to 5 carbon atoms; and the pharmaceutically acceptable acid-additionsalts thereof.

2. A compound according to claim 1 wherein R and R are each hydrogen.

3. A compound according to claim 1 wherein R is hydrogen and R is4-chloro.

4. The compounds according to claim 1 wherein the acid-addition salt ishydrochloride salt.

ALTON D. ROLLINS, Primary Examiner U.S. Cl. X.R.

